N-substituted benzenepropanamide or benzenepropenamide derivatives for use in the treatment of pain and inflammation

ABSTRACT

Compounds for use in the treatment or prophylaxis of pain, including acute and chronic pain (e.g., nociceptive pain, neuropathic pain, headaches, migraine), represented by general formula (I) in which: the dotted line represents a single or a double bond; and R5 and R5′ are independently —H, —OH or —OR 6 , where R 6  is a linear or branched C 1 -C 4  alkyl; X is -0-, —CH 2 O—, —CH 2 CH 2 O—, —CH(CH 3 )CH 2 O— or —CH 2 CH(CH 3 )O—; Z is —CH 2 CH 2 O—, —CH(CH 3 )CH 2 O— or —CH 2 CH(CH 3 )O—; m is an integer of O or 1; and n is an integer of 0-50. The compounds of the invention are also effective for reducing inflammation and may be used alone or in combination with other analgesics.

This application is a continuation of U.S. patent application Ser. No.12/921,004, filed Nov. 2, 2010, now U.S. Pat. No. 8,883,853, which is aU.S. national stage application, filed under 35 U.S.C. 371, ofInternational Application PCT/IB2009/000448, filed Mar. 6, 2009, whichclaims priority under 35 U.S.C. 120 to Great Britain Application No.0804213.7, filed Mar. 6, 2008, the contents of which are incorporatedherein by reference in their entireties.

The present invention relates to the treatment or prophylaxis of painand provides a method of treating or preventing pain as well as the useof certain compounds in the manufacture of medicaments for the treatmentor prophylaxis of pain in humans and non-human animals.

Pain is a multifaceted or multidimensional, experiential response to avariety of stimulus conditions. Pain is defined by the InternationalAssociation for the Study of Pain (IASP) as “an unpleasant sensory andemotional experience associated with actual or potential tissue damage,or described in terms of such damage”.

Pain in animals is frequently the result of nociception, i.e., activityin the nervous system that results from the stimulation of nociceptors.Neuropathic pain differs from nociceptive pain in that it involvesdamage to the nerve resulting in the sensation of pain. In central pain,the pain is generated in the brain from some form of lesion.Occasionally pain may be psychogenic, i.e., caused by mental illness.

Pain can be acute or chronic. Acute pain is usually caused by softtissue damage, infection and/or inflammation among other causes. Acutepain serves to alert after an injury or malfunction of the body. Chronicpain may have no apparent cause or may be caused by a developing illnessor imbalance. Chronic pain is defined as the disease of pain; itsorigin, duration, intensity and specific symptoms may vary.

The experience of physiological pain can be grouped according to thesource and related nociceptors. Cutaneous pain is caused by injury tothe skin or superficial tissues. Cutaneous nociceptors terminate justbelow the skin, and due to the high concentration of nerve endings,produce a well-defined, localised pain of short duration. Examples ofinjuries that produce cutaneous pain include paper cuts, minor cuts,minor (first-degree) burns and lacerations. Somatic pain originates fromligaments, tendons, bones, blood vessels and nerves. It is detected withsomatic nociceptors. The scarcity of pain receptors in these areasproduces a dull, poorly-localised pain of longer duration than cutaneouspain; examples include sprains and broken bones. Myofascial pain isusually caused by trigger points in muscles, tendons and fascia and maybe local or referred. Visceral pain originates from the body's visceraor organs. Visceral nociceptors are located within body organs andinternal cavities. The even greater scarcity of nociceptors in theseareas produces pain that is usually more aching and for longer durationthan somatic pain. Visceral pain is extremely difficult to localise, andseveral injuries to visceral tissue exhibit “referred” pain, where thesensation is localised to an area completely unrelated to the site ofinjury. Phantom limb pain, a type of referred pain, is the sensation ofpain from a limb that has been lost or for which a person no longerreceives physical signals. Neuropathic pain may occur as a result ofinjury or disease to the nerve tissue itself. This can disrupt theability of the sensory nerves to transmit correct information to thethalamus, and hence the brain interprets painful stimuli even thoughthere is no obvious unknown psychological cause for the pain.

Acute pain is usually treated simultaneously with pharmaceuticals orappropriate techniques for removing the cause and pharmaceuticals orappropriate techniques for controlling the pain sensation, commonlyanalgesics.

Analgesics fall into three categories: opioid (narcotic) analgesics,non-opioid analgesics and adjuvant analgesics. Opioid analgesics arepowerful analgesics that are chemically related to morphine. However,opioids have many side effects, which may be more likely to occur inpeople with certain disorders: kidney failure, a liver disorder, chronicobstructive pulmonary disease (COPD), dementia or another braindisorder. Drowsiness, constipation, nausea, vomiting and itching arecommon when opioids are started. Apart from morphine, opioid analgesicsknown at the time of writing include codeine, fentanyl, hydrocodone,hydromorphone, levorphanol, meperidine, methadone, oxycodone,oxymorphone, pentazocine and propoxyphene.

A variety of non-opioid analgesics are also available at the time ofwriting. They are often effective for mild to moderate pain. Mostnon-opioid analgesics are classified as non-steroidal anti-inflammatorydrugs (NSAIDs). An example of an analgesic that is not an NSAID isacetaminophen, which is commonly known as paracetamol. Acetaminophen hassubstantially no anti-inflammatory properties.

NSAIDs are used to treat mild to moderate pain and may be combined withopioids to treat moderate to severe pain. NSAIDs not only relieve pain,but they also reduce the inflammation that often accompanies and worsenspain. Although widely used, NSAIDs can also have side effects, sometimesserious ones, including problems in the digestive tract, bleedingproblems, problems related to retaining fluids and increased risk ofheart and blood vessel disorders. Current NSAIDs include aspirin,ibuprofen, ketoprofen, naproxen, cox-2 inhibitors such as celecoxib,choline magnesium tri salicylate, diflunisal, salsalate, diclofenac,etodolac, fenoprofen, flurbiprofen, indomethacin, ketorolac,meclofenamate, mefenamic acid, meloxicam, nabumetone, oxaprozin,piroxicam, sulindac and tolmetin.

Adjuvant analgesics include antidepressants such, for example, asimipramine, amitriptyline, bupropion, desipramine, fluoxetine andvenlafaxine; anticonvulsants (such as carbamazepine, gabapentin andpregabalin) and oral and topical local anaesthetics.

In the treatment of chronic pain, the “Three-Step Analgesic Ladder”developed by the World Health Organization is often used. For mild pain,acetaminophen, aspirin or other NSAIDs may be employed. For mild tomoderate pain, week opioids such as codeine and dihydrocodeine areemployed in combination with acetaminophen, aspirin or other NSAIDs. Inthe case of moderate to severe pain, strong opioids such as morphine,diamorphine, or fentanyl, hydromorphone, methadone, oxycodone orphenazocine may be administered in combination with acetaminophen,aspirin or other NSAIDs.

An object to the present invention is to provide alternative compoundsfor the treatment or prophylaxis of pain. In particular, it is object tothe present invention to provide alternative NSAIDs for the treatment orprophylaxis of pain and to reduce inflammation. Desirably the compoundsof the invention should have no or substantially no activity on thecentral nervous system.

Another object of the present invention is to provide an alternativemethod for the treatment or prevention of pain.

According to one aspect of the present invention therefore there areprovided compounds for use in the treatment or prevention of pain, whichcompounds may be represented by general formula I below:

in which:

the dotted line represents a single or a double bond; and R₅ and R_(5′)are independently —H, —OH or —OR₆, where R₆ is a linear or branchedC₁-C₄ alkyl;

X is —O—, —CH₂O—, —CH₂CH₂O—, —CH(CH₃)CH₂O— or —CH₂CH(CH₃)O—;

Z is —CH₂CH₂O—, —CH(CH₃)CH₂O— or —CH₂CH(CH₃)O—; m is an integer of 0 or1;

and n is an integer of 0-50.

Suitably, said compounds may be the S-enantiomers of the compoundsrepresented by formula I above. The invention also comprehends the useof the respective pharmaceutically acceptable salts and hydrates of thecompounds of formula I.

The compounds of the present invention may be used for the treatment orprophylaxis of acute or chronic pain. For instance, the compounds may beused for the treatment of nociceptive pain such, for example, ascutaneous pain, somatic pain, myofascial pain, visceral pain, phantomlimb pain or neuropathic pain. The compounds of the invention may alsobe used treatment of headaches or migraine. The compounds may be usedalone or in combination with acetaminophen or another NSAID for thetreatment of mild chronic pain or in conjunction with weak or strongopioids for the treatment of moderate or severe pain.

The compounds of the invention may also be employed in the treatment orprophylaxis of neuropathic pain and may be used in conjunction with oneor more antidepressants or antiepileptic medicaments such, for example,as gabapentin or pregabalin.

According to another aspect of the present invention therefore there isprovided a method for treating or preventing pain in a human ornon-human animal patient, which method comprises administering to saidpatient in need thereof a therapeutic effective amount of one or more ofthe compounds of the invention.

For a human patient, a daily dose of 1.0 mg to 15 g of said one or morecompounds in a pure, substantially pure or partially pure form asdescribed in more detail below may suitably be administered. Thecompounds may be administered under the supervision of a medicalpractitioner in an amount sufficient to achieve effective painmanagement. In some embodiments, the daily dose of said one or morecompounds may be titrated to determine such effective amount. Said dailydose may comprise about 5.0 mg to 1 g, typically about 5 mg to 500 mg.In some embodiments, said dose may comprise 10 mg to 100 mg per day ofsaid one or more compounds. The compounds may be administered on aregimen of one to four times per day.

Said one or more compounds may be administered parenterally,transdermally, intramuscularly, intravenously, intradermally,intranasally, subcutaneously, intraperitoneally, intraventricularly orrectally. Preferably, the one or more compounds are administered orally.

Optionally, the one or more compounds of the present invention may beadministered simultaneously, sequentially or separately with at leastone opioid analgesic, an antidepressant or an antiepileptic medicament.Alternatively, the one or more compounds of the invention may beadministered simultaneously, sequentially or separately with one or moreother NSAIDs or acetaminophen.

In yet another aspect of the present invention there is provided the useof one or more of the compounds of the invention in the manufacture of amedicament for use in the treatment or prophylaxis of pain. Saidmedicament may be manufactured for co-administration with one or more ofacetaminophen, another NSAID, an opioid, an antiepileptic or anantidepressant.

Advantageously, it has been found that the compounds of the presentinvention are effective for reducing or preventing inflammation. It hasalso been found that the compounds of the invention have no orsubstantially no (i.e., within acceptable limits) deleterious effect onthe central nervous system.

As mentioned above, m may be 0; where m=0, n may be 1-50.

Alternatively, m may be 1.

X may be —CH₂O—.

In some embodiments of the invention, the compounds of the invention maybe represented by general formula II below:

in which n, Z, R₅ and R_(5′) are as defined above.

Z may be —CH(CH₃)CH₂O—.

In some embodiments of the present invention, the compounds of theinvention may therefore be represented by general formula III below:

in which n, R₅ and R_(5′) are as defined above.

R₅ may be H. Alternatively, R₅ may be OH.

R_(5′) may be H. Alternatively, R_(5′) may be OH.

Suitably, n may be an integer from 1-50, preferably 1-25. For example, nmay be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24 or 25. Advantageously, n may be 5-9 or 6-8, e.g.,7 or 15-19 or 16-18, e.g., 17.

Alternatively, the compounds of the invention may be the S-enantiomersof the compounds represented by general formulae IV, V, VI and VIIbelow:

in which R is a polyalkylene glycol polymer having n units, wherein n isas defined above, particularly n=1-50.

Suitably, said polyalkylene glycol polymer may be polyisopropyleneglycol.

Suitable synthetic methods for obtaining and purifying the compounds ofthe present invention are disclosed in detail below. However, it shouldbe apparent to a person skilled in the art that the compounds may beprepared using any other feasible synthetic methods.

The compounds of the invention may be synthesised as polyalkylene glycol(PAG) conjugates. Polymers that may be used for such conjugation includepoly(ethylene glycol) (PEG), also known as or poly(ethylene oxide) (PEO)and polypropylene glycol (including poly isopropylene glycol).

A polyalkylene glycol (PAG), such as PEG, is a linear polymer terminatedat each end with hydroxyl groups:HO—CH₂CH₂O—(CH₂CH₂O)_(p)—CH₂CH₂—OH.

The above polymer, α,ω-dihydroxyl poly(ethylene glycol), can also berepresented as HO-PEG-OH, where it is understood that the -PEG- symbolrepresents the following structural unit:—CH₂CH₂O—(CH₂CH₂O)_(p)—CH₂CH₂—

where p may range from 0 to about 48. PEG may be used as methoxy-PEG-OH,or mPEG, in which one terminus is the relatively inert methoxy group,while the other terminus is a hydroxyl group that is subject to readychemical modification. Additionally, random or block copolymers ofdifferent alkylene oxides (e.g., ethylene oxide and propylene oxide)that are closely related to PEG in their chemistry may be substitutedfor PEG.

The PAG polymers may be linear or branched.

It is to be understood that compounds of the invention comprise a PAGmoiety that may include a mixture of polymers which have a varyingnumber of monomeric units. The synthesis of a PAG-conjugate compound mayproduce a population of molecules with a Poisson distribution of thenumber of monomeric units per polymer in the conjugate. Thus, a compoundaccording to the invention that is described as having a polymer of n=7monomeric units refers not only to the actual polymers in thatpopulation being described as having n=7 monomeric units, but also to apopulation of molecules with the peak of the distribution being 7 orclose to 7. The distribution of monomeric units in a given populationcan be determined, e.g., by nuclear magnetic resonance (NMR) or by massspectrometry (MS).

In yet another aspect of the present invention there is provided apharmaceutical composition for use in the treatment or prophylaxis ofpain, said composition comprising a pharmaceutically effective amount ofone or more of the compounds of the invention. Said composition mayfurther comprise one or more pharmaceutically acceptable excipients. Insome embodiments, said composition may also comprise acetaminophen, oneor more other NSAIDs, one or more weak or strong opioids, anantidepressant or an antiepileptic agent.

The pharmaceutical composition of the invention may comprise one or moreof the compounds of the invention in a pure, substantially pure orpartially pure form. In some embodiments, said substantially pure formmay comprise at least 95% wt. of said one or more compounds, e.g., 96%wt., 97% wt., 98% wt. or more than 99% wt. of said compounds.

Said substantially or partially pure form of said compound(s) mayfurther comprise a proportion of free polyalkylene glycol such, forexample, as polyethylene glycol (PEG) or polypropylene glycol (PPG).Such polyalkylene glycol may itself be biologically active. The chainlength of the free polyalkylene glycol may range from 1-50, preferably1-25. In some embodiments, said polyalkylene glycol may have a chainlength of 3, 7, 12 or 17 monomeric units. Said free polyalkylene glycolmay comprise a mixture of different chain lengths. Thus, for asubstantially pure form of said one or more compounds, said form maycomprise up to 5% wt. of free polyalkylene glycol, e.g., up to 4% wt.,3% wt., 2% wt. or less than 1% wt., with the total amount in said formof said one or more compounds and said free polyalkylene glycol being100% wt.

Said partially pure form of said one or more compounds may compriseabout 5-60% wt. of the one or more compounds according to the inventionand about 95-40% wt. of free polyalkylene glycol, the total amount being100% wt. Typically, said partially pure form may comprise about 45-55%wt. of said one or more compounds and about 55-45% wt. of said one ormore polyalkylene glycols. Alternatively, said form may comprise about80-95% wt. of said one or more compounds and about 20-5% wt. of saidpolyalkylene glycol(s).

Suitably, the composition of the invention may be formulated as a unitdosage form. Each unit dosage form may comprise all or a predeterminedfraction of the daily dose amount of the one or more compounds of theinvention, e.g., one half or one quarter of the daily dose amount.

Thus, the composition may be formulated as a tablet, a pill, a capsule,a powder, granules, a sterile parenteral solution or suspension, ametered aerosol or liquid spray, drops, an ampoule, an auto-injectordevice, a suppository, a cream or a gel. Said composition may be adaptedfor oral, enteral parenteral, intrathecal, intranasal, sublingual,rectal or topical administration, or for administration by inhalation orinsufflation. Oral compositions such as tablets, pills, capsules orwafers are particularly preferred.

For preparing a solid dosage form such as a tablet, said one or morecompounds may be mixed with one or more pharmaceutical excipients, e.g.,conventional tabletting ingredients such as corn starch, lactose,sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalciumphosphate or gums, or other pharmaceutical diluents, e.g., water, toform a solid pre-formulation composition containing a substantiallyhomogeneous mixture of said one or more compounds, such that said one ormore compounds are dispersed evenly throughout the composition, so thatthe composition may be readily subdivided into equally effective unitdosage forms such as tablets, pills and capsules.

Said solid pre-formulation composition is then subdivided into unitdosage forms of the kind mentioned above which may each contain from 0.1to about 500 mg of the one or more compounds. Favoured unit dosage formscontain from 1 to 500 mg, e.g., 1, 5, 10, 25, 50, 100, 300 or 500 mg, ofthe compound(s).

When formulated as a tablet or pill, said tablet or pill may be coatedor otherwise compounded to provide a dosage form affording the advantageof prolonged action. For instance, said tablet or pill can comprise aninner dosage and an outer dosage component, the latter being in the formof an envelope over the former. These two components may be separated byan enteric layer that serves to resist disintegration in the stomach andpermits the inner component to pass intact into the duodenum or to bedelayed in release. A variety of materials are known in the use in suchenteric layers or coatings, such materials including a number ofpolymeric acids and mixtures of polymeric acids with such materials asshellac, cetyl alcohol and cellulose acetate.

Alternatively, the pharmaceutical composition of the present inventionmay be formulated as a liquid dosage form for administration orally orby injection; for example an aqueous solution, a suitably flavouredsyrup, an aqueous or oil suspension or a flavoured emulsion with edibleoils such, for example, as cottonseed oil, sesame oil, coconut oil orpeanut oil, as well as an elixir or a similar pharmaceutical vehicle.Suitable dispersing or suspending agents for an aqueous suspensioninclude synthetic and natural gums, e.g., tragacanth, acacia, alginate,dextran, sodium carboxymethylcellulose, methylcellulose,polyvinyl-pyrrolidone or gelatin.

Following is a description by way of example only with reference to theaccompanying drawings of embodiments of the present invention.

In the drawings:

FIG. 1 is a graph showing the results of a Hot-Plate Test using Balb/cmice following administration of Compound 18 of the invention at 100μg/mouse, 1 μg/mouse and 0.01 μg/mouse;

FIG. 2 is a graph showing the results of a Hot-Plate Test using Balb/cmice following administration of Compound 18 of the invention orimipramine;

FIG. 3 is a histogram showing the reduction in the height ofcarrageenan-induced oedemas in SD rats following administration ofCompound 18 of the invention;

FIG. 4 is a histogram showing the reduction in the volume ofcarrageenan-induced oedemas in SD rats following administration Compound18 of the invention;

FIG. 5 is a histogram showing the number of paw licks of Balb/c miceduring a first neurogenic phase following intraplanar injection of 1%formalin (“Formalin test”);

FIG. 6 is a histogram showing the number of paw licks of Balb/c miceduring a second inflammation phase following intraplanar injection of 1%formalin;

FIGS. 7A-N are a series of graphs respectively illustrating thefollowing results of an Open Field Test after the administration ofCompound 18 of the invention (0.1 mg/mouse, 0.5 mg/mouse; i.p., −60 min)to BALB/c mice:

A: distance moved (cm)

B: mean velocity

C: total duration of immobility

D: total duration of strong mobility

E: mean turn angle (degrees)

F: angular velocity (degrees/s)

G: total duration of movement (%)

H: total duration of non-movement (%)

I: in zone frequency (zone 3)

J: rearing frequency

K: in zone duration (zone 3)

L: in zone frequency (zones 2+3)

M: distance moved (cm)

N: in zone duration (zones 2+3)

SYNTHESIS OF POLYALKYLENE GLYCOL COMPOUNDS

Polyalkylene glycol compounds were generally synthesised by preparationof the appropriate alcohol compound (e.g., one of the compoundsdescribed in Synthesis 1 or a hydroxylated derivative thereof) followedby conjugation of the alcohol with a polyalkylene glycol (PAG) polymer(e.g., polyethylene glycol (PEG) or polypropylene glycol (PPG)) of thedesired length.

Synthesis 1 Compound 1 (Phenyl Alaninol)

1.2 g, 32 mM, of LiAlH₄ were added to 2.3 g, 10 mM, phenyl alanine ethylester HCl in 50 ml dry ether. After stirring for 2 hours at roomtemperature, water and KOH were added and the reaction product wasextracted with ethyl acetate. After evaporation, 0.8 g of Compound 1, alight yellow oil, was obtained.

Compound 1 crystallised on standing. Mp-70.

NMR CDCl₃ 7.30 (5H, m), 3.64 (1H, dd, J=10.5, 3.8 Hz) 3.40 (1H, dd,J=10.5, 7.2 Hz) 3.12 (1H, m), 2.81 (1H, dd, J=13.2, 5.2 Hz), 2.52 (1H,dd, J=13.2, 8.6 Hz)

NMR acetone d₆ 7.30 (5H, m), 3.76 (1H, dt) 3.60 (1H, m) 3.30 (1H, t),2.85 (2H, m). Helv. Chim. Acta, 31, 1617(1948). Biels.—E3, Vol. 13, p1757.

Synthesis 2 Compound 2 (Tyrosinol)

To 3 g, 12 mM, L-tyrosine ethyl ester HCl in 50 ml dry ether was added1.2 g 32 mM LiAlH₄. After stirring 3 hours at room temperature, waterand KOH were added and the reaction was extracted with ethyl acetate.Evaporation gave 1.1 g of a light yellow oil, 54% yield, which onstanding crystallized. mp-85.

NMR CDCl₃ 7.20 (4H, AB q, J=8.6 Hz), 3.50 (2H, m) 3.20 (1H, m), 2.81(2H, m).

NMR tyrosine ethyl ester free base CDCl₃ 7.0, 6.56 (4H, AB q, J=8.8 Hz),4.20 (2H, q, J=7, 0 Hz), 3.70, 3.0, 2.80 (3H, 12 line ABXm), 1.28. (3H,t, J=7.0 Hz). JACS 71, 305(1949). Biels.—E3, Vol. 13, p 2263.

Synthesis 3 Compound 3 (Tryptophanol)

To 3 g, 12.9 mM, L-tryptophan methyl ester HCl in 50 ml dry ether wasadded 1.2 g, 32 mM LiAlH₄. After stirring 6 hours at room temperaturewater and KOH were added and the reaction extracted with ethyl acetate.Evaporation gave 1.23 g light yellow oil, 50% yield. On standingcrystallized. Mp-65.

NMR CDCl₃ 7.30 (5H, m), 3.64 (1H, dd, J=10.5, 3.8 Hz) 3.40 (1H, dd,J=10.5, 7.2 Hz) 3.12 (1H, m), 2.81 (1H, dd, J=13.2, 5.2 Hz), 2.52 (1H,dd, J=13.2, 8.6 Hz) J. Het. Chem, 13, 777 (1976). Biels.—E5, 22, Vol.12, p 90.

Synthesis 4 Compound 4

0.66 g 4-hydroxy hydrocinnamic acid and 4 ml thionyl chloride in 30 mlcyclohexane were refluxed for 2 hours. After evaporation, a white solidwas obtained, to which 0.65 g oil of Compound 1 (4.3 mM) in 30 mldichloromethane and 0.4 ml triethyl amine were added. After stirring for2 hours at room temperature, water and KOH were added in order toneutralize the pH. The reaction product was extracted withdichloromethane. Evaporation gave 0.8 g of Compound 4, light yellowviscous oil. Part of this product was triturated and recrystallized withethanol to give a white solid. Mp-149.

NMR CDCl₃ 7.30-6.9 (9H, m), 3.50 (2H, m) 3.30 (2H, t, J=7.2 Hz) 2.90(3H, m), 2.60 (2H, t, J=7.2 Hz).

Synthesis 5 Compound 5

0.75 g, 5 mM, hydrocinnamic acid and 4 ml thionyl chloride in 30 mlcyclohexane were refluxed for 2 hours. Evaporation gave a white solid towhich were added 0.83 g, 5.5 mM, phenyl alaninol in 30 mldichloromethane and 0.5 ml triethyl amine. After stirring 3 hours atroom temperature, water and KOH were added to neutral pH and thereaction was extracted with dichloromethane. Evaporation gave 0.57 g ofa yellow viscous oil, 40% yield.

NMR CDCl₃ 7.40-7.10 (10H, m), 3.60 (2H, m) 3.35 (2H, t, J=7.2 Hz) 2.95(3H, m), 2.50 (2H, t, J=7.2 Hz).

Synthesis 6 Compound 6

0.66 g, 4 mM, 4-hydroxy hydrocinnamic acid and 4 ml thionyl chloride in30 ml cyclohexane were refluxed 3 hours. Evaporation gave a light yellowsolid to which were added 0.72 g, 4.3 mM, tyrosinol in 30 mldichloromethane and 0.5 ml triethyl amine. After stirring 3 hours atroom temperature. water and KOH were added to neutral pH and thereaction was extracted with dichloromethane. Evaporation gave 0.53 glight yellow viscous oil, 42% yield.

NMR CDCl₃ 7.30, 7.20 (8H, 2 ABq, J=8.6 Hz), 3.40 (2H, m) 3.30 (2H, t,J=7.2 Hz) 2.90 (3H, m), 2.60 (2H, t, J=7.2 Hz).

Synthesis 7 Compound 8

0.45 g, 3 mM, hydrocinnamic acid and 3 ml thionyl chloride in 30 mlcyclohexane were refluxed for 2 hours. Evaporation gave a light yellowsolid to which were added 0.58 g, 3.5 mM, tyrosinol in 30 mldichloromethane and 0.4 ml triethyl amine. After stirring for 2.5 hoursat room temperature, water and KOH were added to attain neutral pH andthe reaction was extracted with dichloromethane. Evaporation gave 0.57 glight yellow viscous oil, 63% yield.

NMR CDCl₃ 7.40-7.10 (9H, m), 3.60 (2H, m) 3.35 (2H, t, J=7.2 Hz) 2.95(3H, m), 2.50 (2H, t, J=7.2 Hz).

Synthesis 8 Compound 10

0.3 g of Compound 4, 0.8 g, triphenyl phosphine and 0.55 g ethyl diazocarboxylate were added to 1 g of poly(propylene glycol), (averagemolecular weight ca 1000), in 60 ml dichloromethane. Stirring for 2hours at room temperature, evaporation and chromatography gave 0.65 g ofCompound 10 as a viscous oil.

Compounds Synthesised from Phenyl Alaninol

These compounds include those represented by the structure of formulaVIII:

This compound can also be represented as formula A, where R is apolypropylene glycol polymer and n is the total number of polypropylenemonomers in the polymer:

Synthesis 9 Compound 11

R=PPG (polypropylene glycol); n=7; MW=706

0.3 g Compound 4 (1 mM), 0.8 g, 3 mM, triphenyl phosphine and 0.55 g 3.2mM, ethyl diazo carboxylate were added to 1 g of poly (propylene glycol)(average mol. Weight 424, n=7) in 60 ml dichloromethane. After stirringfor 4 hours at room temperature, evaporation and chromatography gave0.55 g viscous oil, a 73% yield. NMR CDCl₃ 7.30-6.9 (9H, m), 4.1-3.0(m), 2.60 (2H, t, J=7.2 Hz), 1.2-1.1 (m). 0.1 g, 0.33 mmol of thisproduct, potassium carbonate (0.069 g, 0.5 mmol, thinly crushed) and THF(3 mL, dried over KOH pellets) were put in a round-bottom flask equippedwith a magnetic stirrer and a CaCl₂ drying tube. The mixture was cooledover an ice-salt bath (−10° C.) and a pre-cooled solution ofdi-tert-butyldicarbonate (0.066 g, 0.30 mmole) in 2 mL THF (dried) wasintroduced dropwise. The mixture was allowed to stir at ice temperaturefor 1 hour and then for 2 days at room temperature. The reaction mixturewas then evaporated, water (5 mL) introduced and the product wasextracted with two 10 mL portions of ethyl acetate. The combinedextracts were dried over anhydrous magnesium sulfate, paper-filtered andthe solvent removed. The oily residue was triturated with a small amountof n-hexane and the solid formed recovered by vacuum filtration (yield0.12 g, 90.1%). Alternatively, the oily residue can be dissolved in an1:1 mixture of ethyl acetate and hexane and the product recrystallised.

Synthesis 10 Compound 12

R=PPG; n=12; MW=996

Compound 12 was prepared as described in Synthesis 9 above for Compound11 from 0.2 g Compound 10 to give a 0.3 g, 46% yield.

Synthesis 11 Compound 13

R=PPG; n=17; MW=1286

Compound 13 was prepared using the same procedure as described above inSynthesis 9 for Compound 11, with the substitution of the PPG, n=7 forPPG, n=17.

Compounds Synthesised from Compound 5

Synthesis 12 Compound 14

R=PPG; n=7; MW=690

Compound 14 was prepared as described above in Synthesis 9 from 0.22 gCompound 5 to give a 0.25 g, 47% yield.

Synthesis 13 Compound 15

R=PPG; n=17; MW=1270

Compound 15 was prepared as above in Synthesis 9 from 0.2 g Compound 5to give 0.33 g, 33% yield.

Compounds Synthesised from Compound 6 (Tyrosinol)

Synthesis 14 Compound 16

R=PPG; n=7; MW=722

Compound 16 was prepared as described above in Synthesis 9 from 0.2 gCompound 6 to give a 0.21 g, 46% yield.

Synthesis 15 Compound 17

R=PPG; n=17; MW=1302

Compound 17 was prepared as described above in Synthesis 9 from 0.23 gCompound 6 to give a 0.28 g, 29% yield.

Compounds Synthesised from Compound 8

Synthesis 16 Compound 18

R=PPG; n=7; MW=706

Mesylation of PPG

106 mg of PPG₄₂₅ (0.25 mmol) was reacted with 90 mole-percent of mesylchloride (26 mg, 2 drops) and 0.4 mmol pyridine (31.6 mg, 2 drops) toafford the mono-mesylated PPG (A). After combining PPG, mesyl chlorideand pyridine, the mesylation reaction was carried out at 0° C. over 30minutes while stirring, and then the reaction was continued for another60 minutes at room temperature. During mixing, the reaction mixtureturned from colorless to milky-white. The mixture was then dissolved in5 mL methylene chloride and the organic phase was washed twice with 1MHCl solution, then twice with 1M NaOH solution and once with water. Theorganic phase was dried over anhydrous sodium sulfate, filtered and thesolvent removed.

Sodium Activation.

0.1 g of the above product (0.25 mmol) was dissolved in 5 mL of absoluteethanol and then reacted with an equimolar amount of sodium ethoxide inabsolute ethanol (previously prepared by reacting 0.25 mg-atom of sodiumwith an access of absolute ethanol). The ethanol of the combinedsolutions was evaporated to total dryness to yield the sodium salt (B).

Reacting A and B

A was dissolved in 5 mL of a potassium hydroxide-dried acetonitrile andthe solution introduced into a round-bottom flask containing a magneticstirrer. 5 mL of dried acetonitrile solution of B was introduced intothe flask, followed by a catalytic amount (few crystals) of potassiumiodide. A reflux condenser and a gas bubbler adjusted on top of it wereconnected to the reaction vessel and the reaction mixture was allowed toreflux under nitrogen atmosphere, while stirring, for 24 hrs. Thereaction mixture was then paper-filtered and the solvent removed. Theresidue was dissolved in 2 mL of ethyl acetate and then passed through asilica-gel column, using ethyl acetate for elution. The TLC (elutionwith ethyl acetate) UV-absorbing spot at R_(f)=0.55 turned out tocontain the desired product 3 (a mixture of molecules containingdifferent PPG sub-unit lengths), however, containing also some unreactedPPG. Other fractions contained unreacted mesylated PPG anddoubly-mesylated PPG.

Synthesis 17 Compound 19

R=PPG; n=17; MW=1000

Compound 19 was prepared using the same procedure as described above inSynthesis 16 for Compound 18, with the substitution of the PPG, n=7 forPPG, n=17.

The following experiments were conducted to demonstrate the utility ofcompounds of the invention in the treatment of pain.

EXAMPLE 1 Hot-Plate Test of Balb/c Mice

21-week old male Balb/c mice (non-naive) were divided into four groupsof approximately 7 or 8 mice per group and treated at t=0 minutes withCompound 18 intraperitoneally with 0.2 mL solution as detailed in Table1 below:

TABLE 1 Group 1 Control 0.2 mL/mouse (20 μL DMSO + 1980 μm saline) 2 100μg/mouse 191 μL (10.5 mg Compound 18 + 200 μL Compound 18 DMSO + 1800 μLsaline) + 1809 μL saline 3 1 μg/mouse 20 μL (Compound 18 100 μg/mouse) +Compound 18 1980 μL saline 4 0.01 μg/mouse 20 μL (Compound 18 1μg/mouse) + Compound 18 1980 μL saline

The mice were tested using a hot-plate (J. P. Callaghan & S. G.Holtzman, “Quantification of the Analgesic Activity of NarcoticAntagonists by a Modified Hot-Plate Procedure”, J. Pharmacol. Exp.Ther., 1975; 192(3): 497-505) at t=−60 mins., 0 mins., 60 mins., 120mins., 180 mins., 240 mins. and 300 mins. The results are set forth inTable 2 below and illustrated in FIG. 1 of the accompanying drawings.The numbers in the columns are time taken (in seconds) for the mice toreact to the hot-plate. A licking of the fore or hind paws was used asthe end-point for the determination of response latencies.

TABLE 2 Group # mouse −60 0 60 120 180 240 300 1 25 18 27 28 24 20 24 225 22 23 35 25 22 32 3 33 20 31 24 24 23 20 Control 4 22 23 20 21 20 1916 10% DMSO 5 21 22 21 25 24 28 23 6 27 25 22 22 21 24 23 7 26 24 23 2215 20 24 8 22 25 21 22 21 17 14 Average 25.1 22.4 23.5 24.9 21.8 21.622.0 SD 3.8 2.4 3.7 4.7 3.3 3.4 5.5 SE 1.4 0.9 1.3 1.7 1.2 1.2 2.0 9 2819 15 18 25 30 22 10 21 26 24 19 26 32 28 11 24 25 21 26 37 43 23 100μg/mouse 12 23 22 24 24 29 41 35 13 22 21 18 31 37 26 34 14 21 15 23 3041 36 29 15 31 28 29 28 28 56 33 Average 24.3 22.3 22.0 25.1 31.9 37.729.1 SD 3.8 4.5 4.5 5.1 6.3 10.0 5.2 SE 1.4 1.7 1.7 1.9 2.4 3.8 2.0t-test vs. Control 0.6786 0.9634 0.5011 0.9178 0.0045 0.0046 0.0232 1627 13 29 26 35 19 17 17 21 18 17 26 35 34 28 18 19 24 19 34 36 42 41 1μg/mouse 19 26 19 22 30 31 35 40 20 22 22 19 33 38 42 24 21 33 35 29 6486 44 37 22 22 24 21 27 28 47 18 Average 24.3 22.1 22.3 34.3 41.3 37.629.3 SD 4.8 6.9 4.9 13.5 20.0 9.4 10.2 SE 1.8 2.6 1.8 5.1 7.6 3.6 3.8t-test vs. Control 0.7159 0.9346 0.6007 0.1212 0.0415 0.0034 0.1252 2318 24 18 25 36 31 27 24 26 21 13 11 22 34 26 25 29 28 26 35 28 32 290.01 μg/mouse 26 19 22 34 36 24 22 24 27 33 16 16 34 37 20 22 28 24 3526 21 36 27 17 29 21 15 20 24 22 24 25 Average 24.3 23.0 21.9 26.6 29.327.1 24.3 SD 5.5 6.9 7.2 9.1 6.9 5.4 3.9 SE 2.1 2.6 2.7 3.4 2.6 2.0 1.5t-test vs. Control 0.7408 0.8269 0.6010 0.6677 0.0287 0.0417 0.3683

As those skilled in the art will recognise, these data show thatCompound 18 according to the invention shows analgesic activity in mice.

EXAMPLE 2 Hot-Plate Test of Balb/c Mice Vs. Imipramine (i.p. & p.o.)

14-week old male Balb/c mice (non-naive) were divided into four groupsof seven mice per group and treated at t=0 as detailed in Table 3 below:

TABLE 3 Group 1 Control i.p.: 0.3 mL/mouse (20 μL DMSO + 2680 μL saline)p.o.: 0.3 mL/mouse (20 μL DMSO + 2680 μL saline) 2 5 mg/kg i.p.: 5 mg/kg(1.35 mg imipramine + Imipramine 2.7 mL saline) p.o.: 0.3 mL/mouse (20μL DMSO + 2680 μL saline) 3 0.5 mg/mouse i.p.: 0.3 mL/mouse (0.479 mLCompound 18 (i.p.) Compound 18 stock + 2.221 mL' saline) p.o.: 0.3mL/mouse (20 μL DMSO plus 2680 μL saline) 4 0.5 mg/mouse i.p.: 0.3mL/mouse (20 μL DMSO Compound 18 (p.o.) plus 2680 μL saline) p.o.: 0.3mL/mouse (0.479 mL Compound 18 stock + 2.221 mL saline)

Compound 18 stock comprises 9.4 mg Compound 18, 0.2 mL DMSO and 0.8 mLsaline.

As in Example 1 above, the response latencies of the mice in therespective groups were tested using a hot-plate at t=−60 mins., 0 mins.,60 mins., 120 mins., 180 mins., 240 mins., 300 mins. and 360 mins. Theresults are set forth in Table 4 below and are illustrated in FIG. 2 ofthe drawings.

TABLE 4 Group # mouse weight −60 0 60 120 180 240 300 360 1 24.3 19 1619 32 30 31 32 25 2 23.5 12 8 18 23 25 29 34 27 A 3 21.5 17 15 21 41 4954 42 36 0.5 mg/mouse/p.o. 4 20.9 19 7 20 26 40 42 38 35 5 21.2 16 14 2238 37 47 56 47 6 25.6 25 18 22 42 44 37 41 50 n = 7 7 25.6 17 17 18 2956 55 44 32 Average 23.2 17.9 13.6 20.0 33.0 40.1 42.1 41.0 36.0 SD 2.03.9 4.4 1.7 7.5 10.7 10.4 7.9 9.5 SE 0.7 1.4 1.5 0.6 2.6 3.8 3.7 2.8 3.3t-test vs. Control 0.3832 0.5115 0.0027 0.0011 0.0025 0.0014 0.00010.0072 8 24.3 20 18 10 14 18 22 24 25 Control 9 24.5 22 16 11 21 24 2321 21 B 10 24.8 32 23 12 18 17 21 14 12 11 21.7 25 10 10 12 22 17 17 2512 24 11 12 19 23 24 20 18 13 13 25 19 13 16 24 21 21 15 26 n = 7 1423.2 15 14 17 13 19 20 23 29 Average 23.9 20.6 15.1 13.6 17.9 20.7 20.618.9 21.6 SD 1.1 6.8 4.3 3.7 4.9 2.8 1.9 3.9 6.6 SE 0.4 2.6 1.6 1.4 1.91.1 0.7 1.5 2.5 15 25.5 21 13 14 19 20 21 22 25 16 24.1 15 14 16 16 1816 25 18 C 17 23.5 26 16 16 12 14 19 21 16 18 22.6 24 15 16 10 19 16 2530 Imipramine 5 mg/kg 19 22.9 19 12 20 20 22 31 21 18 20 21.5 17 14 1014 24 22 21 20 n = 7 21 22.9 13 12 12 11 28 35 27 16 Average 23.3 19.313.7 14.9 14.6 20.7 22.9 23.1 20.4 SD 1.3 4.7 1.5 3.2 3.9 4.5 7.4 2.55.2 SE 0.4 1.7 0.5 1.1 1.4 1.6 2.6 0.9 1.8 t-test vs. Control 0.68920.4357 0.5017 0.1945 1.0000 0.4543 0.0334 0.7267 22 21 28 14 21 33 35 3837 34 0.5 mg/mouse/i.p. 23 23.2 19 15 26 29 56 70 57 38 24 23.9 9 11 2137 38 37 28 33 D 25 24.2 14 8 28 44 67 44 58 38 26 23.2 16 12 23 43 5244 40 35 27 22.5 23 16 27 33 49 48 41 51 n = 7 28 26.5 12 10 25 36 45 4336 40 Average 23.5 17.3 12.3 24.4 36.4 48.9 46.3 42.4 38.4 SD 1.7 6.62.9 2.8 5.5 10.9 11.1 11.1 6.1 SE 0.5 1.9 0.8 0.8 1.6 3.2 3.2 3.2 1.8t-test vs. Control 0.3763 0.1756 0.0001 0.0000 0.0003 0.0008 0.00090.0003

Compound 18 thus showed analgesic activity, not only against negativecontrol, but also against imipramine (p<0.0000) as a positive control.

Further, the results of Example 2 also show that Compound 18 manifestedactivity by the oral route at almost the same level of magnitude as viaintraperitoneal injection.

EXAMPLE 3 Oedema Test

The ability of the compounds of the invention to treat inflammation wastested using the carrageenan-induced paw oedema test in rats (see, e.g.,P. G. Winyard & D. A. Willoughby, “Inflammation Protocols”, Methods inMolecular Biology, 2003; Vol. 225).

21-week-old male Sprague-Dawley (SD) rats (non-naive) were divided intofour groups of seven rats per group untreated at t=−2 hr as detailed inTable 5 below:

TABLE 5 Group 1 Control 2 0.1 μg/0.4 mL/rat 32 μL (Compound 18 Compound18 10 μg/0.4 mL/rat) + 3168 μL saline 3 10 μg/0.4 mL/rat 32 μL (Compound18 1 mg/0.4 mL/rat) + Compound 18 3168 μL saline 4 1 mg/0.4 mL/ratCompound 18 stock solution (8.9 mg + Compound 18 178 μL DMSO + 712 μLsaline = 8.9 mg/890 μL)

At t=0 (i.e., 2 hours after administration of the control/Compound 18formulations) paw oedema was induced by injecting 200 μL of a 1% (60mg+6000 μL) solution of λ-carrageenan in normal saline into the plantarsurface of the left hind paw of the rats. The area and the height of theinduced oedema was measured at t=4, 24 and 48 hours after injectionusing a caliper. The anti-inflammatory activity of the injected Compound18 formulation was expressed as the amount of reduction relative to thecontrol in the height and volume of the oedema, the volume beingcalculated as the product of the oedema measured height and area.

The results are set forth in Tables 6 to 9 below and are illustratedgraphically in FIGS. 3 and 4 of the accompanying drawings. Table 6 givesthe data for the measured oedema heights (in mm), and Table 7 and FIG. 3give the corresponding average figures for each group of rats.

Table 8 gives the data for the measured oedema volumes (in mm³) andTable 9 and FIG. 4 give the corresponding average figures for each groupof rats.

TABLE 7 Average Reduction in Oedema Height with Time 4 h/mm 24 h/mm 48h/mm Control 2.6 3.5 2.6 0.1 μg/0.4 ml/rat 2.8 2.0 1.8  10 μg/0.4 ml/rat4.4 3.6 4.0   1 mg/0.4 ml/rat 3.4 1.6 1.1

TABLE 9 Average Reduction in Oedema Volume with Time 4 h/mm³ 24 h/mm³ 48h/mm³ Control 1366.2 1711.6 1249.2 0.1 μg/0.4 ml/rat 1334.4 1158.31154.9  10 μg/0.4 ml/rat 1527.0 1400.2 1451.3   1 mg/0.4 ml/rat 1371.71171.1 897.5

These data confirm the anti-inflammatory properties of Compound 18.

TABLE 6 Group # rat H 0 h H 4 h H 24 h H 48 h H 4 h − H 0 h H 24 h − H 0h H 48 h − H 0 h 1 5.15 6.65 7.4 6.36 1.5 2.25 1.2 2 3.69 5.55 7.58 5.721.86 3.89 2.0 3 3.73 5.93 6.61 5.76 2.2 2.88 2.0 Control 4 3.4 6.85 7.778.05 3.45 4.37 4.7 5% DMSO 5 3.7 6.8 8.09 7.71 3.1 4.39 4.0 6 3.6 7.47.5 6.27 3.8 3.9 2.7 7 4.2 6.6 6.78 6.04 2.4 2.58 1.8 Average 3.9 6.57.4 6.6 2.6 3.5 2.6 SD 0.6 0.6 0.5 0.9 0.9 0.9 1.2 SE 0.2 0.2 0.2 0.40.3 0.3 0.5 8 4.4 6.05 6.02 6.1 1.65 1.62 1.7 9 5.5 9.03 8.18 6.57 3.532.68 1.1 10 5.56 6.6 6.57 4.81 1.04 1.01 −0.8 0.1 μg/0.4 ml/rat 11 4.67.5 5.86 5.87 2.9 1.26 1.3 12 4.5 8.3 7.35 9.98 3.8 2.85 5.5 13 3.6 6.46.13 5.48 2.8 2.53 1.9 14 4.9 8.5 7.19 7.1 3.6 2.29 2.2 Average 4.7 7.56.8 6.6 2.8 2.0 1.8 SD 0.7 1.2 0.9 1.7 1.0 0.7 1.9 SE 0.3 0.4 0.3 0.60.4 0.3 0.7 t-test vs. Control 0.0374 0.0899 0.1251 1.0000 0.7826 0.00650.3689 15 4.5 7.6 8.43 7.14 3.1 3.93 2.6 16 3.4 10.2 8.17 10.7 6.8 4.777.3 17 3.6 8.07 6.18 8.02 4.47 2.58 4.4 10 μg/0.4 ml/rat 18 3.68 8.26 77.4 4.58 3.32 3.7 19 4.63 7.42 7.26 7.66 2.79 2.63 3.0 20 3.98 8.9 7.597.49 4.92 3.61 3.5 21 3.99 8.04 8.2 7.56 4.05 4.21 3.6 Average 4.0 8.47.5 8.0 4.4 3.6 4.0 SD 0.5 0.9 0.8 1.2 1.3 0.8 1.5 SE 0.2 0.4 0.3 0.50.5 0.3 0.6 t-test vs. Control 0.8784 0.0015 0.6733 0.0308 0.0134 0.80680.0896 22 4.92 7.6 6.39 6.06 2.68 1.47 1.1 23 4.9 7.8 6.84 6 2.9 1.941.1 24 5.45 7.6 5.07 5.6 2.15 −0.38 0.1 1 mg/0.4 ml/rat 25 4.9 8.6 7.596.55 3.7 2.69 1.7 26 3.7 9.57 7.29 6.32 5.87 3.59 2.6 27 4.8 8.46 6.195.37 3.66 1.39 0.6 28 5.66 8.4 6.15 6.05 2.74 0.49 0.4 Average 4.9 8.36.5 6.0 3.4 1.6 1.1 SD 0.6 0.7 0.8 0.4 1.2 1.3 0.8 SE 0.2 0.3 0.3 0.20.5 0.5 0.3 t-test vs. Control 0.0108 0.0004 0.0388 0.1801 0.2007 0.01050.0209

TABLE 8 Group # rat V 4 h V 24 h V 48 h V 24 h − V 4 h V 48 h − V 4 h 11277.2 2645.4 1316.2 1368.2 39.0 2 988.4 1776.3 1159.6 787.9 171.2 31229.7 1296.3 1104.6 66.6 −125.1 Control 4 1556.0 1790.4 1588.0 234.432.1 5% DMSO 5 1841.5 1816.8 1484.2 −24.8 −357.3 6 1627.4 1347.0 1017.5−280.4 −609.9 7 1043.0 1309.2 1074.1 266.2 31.1 Average 1366.2 1711.61249.2 345.5 −117.0 SD 317.3 476.2 219.0 557.8 274.6 SE 119.9 180.0 82.8210.8 103.8 8 1343.9 1064.9 968.3 −279.0 −375.6 9 1686.4 1263.4 979.1−422.9 −707.3 10 985.4 1189.3 637.8 203.9 −347.7 0.1 μg/0.4 ml/rat 111212.5 927.6 820.7 −284.9 −391.8 12 1456.5 1354.7 2394.0 −101.8 937.5 131160.8 1029.1 810.8 −131.7 −350.0 14 1495.3 1279.2 1473.6 −216.1 −21.7Average 1334.4 1158.3 1154.9 −176.1 −179.5 SD 235.1 154.8 605.6 198.7531.0 SE 88.8 58.5 228.9 75.1 200.7 t-test vs. Control 0.8352 0.02140.7092 0.0502 0.7884 15 1113.1 1403.9 1157.6 290.8 44.5 16 1689.2 1450.02222.9 −239.2 533.7 17 1622.1 1117.3 1388.0 −504.8 −234.1 10 μg/0.4ml/rat 18 1486.4 1355.2 1404.7 −131.2 −81.6 19 1396.5 1295.4 1391.4−101.1 −5.1 20 1792.1 1493.4 1389.7 −298.7 −402.4 21 1589.9 1686.11205.0 96.2 −384.9 Average 1527.0 1400.2 1451.3 −126.9 −75.7 SD 223.4176.1 354.9 261.4 321.0 SE 84.5 66.5 134.2 98.8 121.3 t-test vs. Control0.2966 0.1452 0.2286 0.0749 0.8003 22 1369.9 1154.3 824.5 −215.6 −545.423 1241.3 1256.1 839.9 14.8 −401.4 24 1246.3 885.4 947.9 −360.9 −298.4 1mg/0.4 ml/rat 25 1508.5 1408.3 962.3 −100.2 −546.2 26 1382.2 1411.4971.2 29.2 −411.0 27 1523.3 1157.6 802.7 −365.8 −720.7 28 1330.6 924.5934.3 −406.1 −396.2 Average 1371.7 1171.1 897.5 −200.6 −474.2 SD 112.7209.8 72.1 184.7 139.8 SE 42.6 79.3 27.2 69.8 52.8 t-test vs. Control0.9664 0.0244 0.0046 0.0422 0.0136

EXAMPLE 4 Formalin Test

27-week old Balb/c mice (non-naive) were divided into four groups of 5mice per group and treated at t=0 mins. with intraperitoneal control orCompound 18 solution as set forth in Table 10 below.

TABLE 10 Group 1 Control 0.2 mL/mouse i.p. (0.2 mL DMSO + 3.52 mLsaline) 2 0.02 mg/0.2 mL/mouse 0.04 mL (Compound Compound 18 18 0.5mg/0.2 mL/mouse) + 0.96 mL saline 3 0.1 mg/0.2 mL/mouse 0.2 mL (CompoundCompound 18 18 0.5 mg/0.2 mL/mouse) + 0.8 mL saline 4 0.5 mg/0.2mL/mouse Compound 18 9.3 mg + 0.2 mL Compound 18 DMSO + 3.5 mL saline

Following the method of S. Hunscaar & K. Hole, “The Formalin Test inMice: Dissociation between Inflammatory and Non-Inflammatory Pain”,Pain, 1987; 30:103-104, 20 λL of formalin 1% was injected via theintraplantar route subcutaneously into the right hind paw of each mouse3 hours after administration of the control/Compound 18 solution. Themice were then returned to a glass chamber, and the formalin-inducedflinching behaviour of the injected paw was counted.

Formalin-induced pain is biphasic; the amount of the paw-licking wasdetermined during a first neurogenic phase (0-5 mins.) and subsequentlyduring a second inflammatory phase (20-30 mins.) after formalininjection. The results are set forth in Table 11 below and illustratedgraphically in FIGS. 5 and 6 of the drawings.

TABLE 11 Group # mouse weight treatment formalin 5 min inflam. 10 min 127.8 08:20 11:20 342 11:40 62 2 30.8 08:30 11:30 348 11:50 116 Control 325.5 08:40 11:40 346 12:00 119 4 27.8 08:50 11:50 363 12:10 229 5 mice 528 09:00 12:00 329 12:20 138 Average 28.0 345.6 132.8 SD 1.9 12.2 60.8SE 0.8 5.5 27.2 6 27.3 09:10 12:10 161 12:30 87 7 26.6 09:20 12:20 18912:40 120 0.02 mg/0.2 ml/mouse 8 25.7 09:30 12:30 166 12:50 25 9 28.809:40 12:40 246 13:00 170 5 mice 10 28.2 09:50 12:50 214 13:10 67Average 27.3 195.2 93.8 SD 1.2 35.3 54.8 SE 0.6 15.8 24.5 t-test vs.Control 0.533363 0.000301 0.317755 11 26.9 10:50 13:50 86 14:10 64 1229.2 11:00 14:00 117 14:20 13 0.1 mg/0.2 ml/mouse 13 28.5 11:10 14:10146 14:30 59 14 29.3 11:20 14:20 115 14:40 116 5 mice 15 29.5 11:3014:30 140 14:50 157 Average 28.7 120.8 81.8 SD 1.1 23.8 55.7 SE 0.5 10.624.9 t-test vs. Control 0.4950 0.0000 0.2040 16 28.5 11:40 14:40 9915:00 101 17 30.7 11:50 14:50 131 15:10 55 0.5 mg/0.2 ml/mouse 18 28.812:00 15:00 116 15:20 93 19 26.3 12:10 15:10 84 15:30 12 5 mice 20 26.412:20 15:20 86 15:40 24 Average 28.1 103.2 57.0 SD 1.8 20.1 39.8 SE 0.89.0 17.8 t-test vs. Control 0.8952 0.0000 0.0529

These data further confirm the anti-inflammatory properties of Compound18.

EXAMPLE 5 Open Field (“OF”) Test

24 six-week old male BALB/c mice were divided into three groups of 8mice per group and were treated at t=−90 mins. as set forth in Table 12below.

TABLE 12 Group 1 Control 0.2 mL/mouse i.p. (20 μL DMSO + 980 μL saline)2 0.1 mg/0.1 mL/mouse 0.1 mL/mouse (0.111 mL Compound 18 Compound 18stock solution + 0.889 mL saline) 3 0.5 mg/0.1 mL/mouse 0.1 mL/mouse(0.555 mL (Compound Compound 18 18 stock solution 9.0 mg + 0.2 mL DMSO +0.80 mL saline) + 0.445 mL saline)

The mice were then subjected to an Open Field test for 60 minutes infour arenas, with the mice distributed as follows:

TABLE 13 OF OF Arena Arena Arena Arena Treatment start finish 1 2 3 4time time time 1 Control 0.1 mg 0.5 mg Control 08:00 09:30 10:30 2 0.1mg 0.5 mg Control 0.1 mg 09:05 10:35 11:35 3 0.5 mg Control 0.1 mg 0.5mg 10:10 11:40 12:40 4 Control 0.1 mg 0.5 mg Control 11:15 12:45 13:45 50.1 mg 0.5 mg Control 0.1 mg 12:20 13:50 14:50 6 0.5 mg Control 0.1 mg0.5 mg 13:25 14:55 15:55

An Open Field test measures activity in a novel environment and can beused to assess a combination of locomotor activity, exploratory drive,neophobia, agoraphobia and other aspects of anxiety or fear in mice, aswell as motor function. The apparatus consists of a Perspex arena(approximately 44 cm×44 cm×50 cm high).

The activity of the mice was assessed by an EthoVision video tracksystem (Noldus Ltd.) A centre zone (“zone 3”; approximately 16% of thetotal area), a border area (“zone 1”; an 8 cm wide border around theedge of the arena) and an intermediate zone (“zone 2”; the remainingarea) were defined. Quantitative parameters, such as the distancetraveled and average speed, were recorded for the centre zone and theentire arena.

The distance moved, mean velocity, total duration of immobility, totalduration of strong mobility, mean turn angle, angular velocity, totalduration of moving, total duration of not moving, in zone frequency for“zone 3”, rearing frequency, in zone duration for “zone 3”, in zonefrequency for “zones 2+3”, distance moved and in zone duration for“zones 2+3” are illustrated graphically in FIGS. 7A to 7N of theaccompanying drawings respectively.

The results indicate that Compound 18 has no activity on the centralnervous system.

The invention claimed is:
 1. A method for treating or preventingneuropathic pain in a human or non-human animal patient in need thereof,which method comprises administering to said patient a therapeuticeffective amount of at least one compound represented by formula I:

or a pharmaceutically acceptable salt thereof in which: the dotted linerepresents a single or a double bond; and R₅ and R₅′ are independently—H, —OH or —OR₆, where R₆ is a linear or branched C₁-C₄ alkyl; X is —O—,—CH₂O—, —CH₂CH₂O—, —CH(CH₃)CH₂O— or —CH₂CH(CH₃)O—; Z is —CH₂CH₂O—,—CH(CH₃)CH₂O— or —CH₂CH(CH₃)O—; m is an integer of 0 or 1; and n is aninteger of 1-50.
 2. The method of claim 1 for the treatment of acute orchronic neuropathic pain.
 3. The method of claim 1, wherein m is 0 and nis 1-50.
 4. The method of claim 1, wherein m is
 1. 5. The method ofclaim 1, wherein X is —CH₂O—.
 6. The method of claim 4, wherein saidcompound is represented by formula II:


7. The method of claim 1, wherein Z is —CH(CH₃)CH₂O—.
 8. The method ofclaim 6, wherein said compound is represented by formula III:


9. The method of claim 1, wherein R₅ is H or OH.
 10. The method of claim1, wherein R₅′ is H or OH.
 11. The method of claim 1, wherein thecompound is represented by formula IV, V, VI or VII:

in which R is a polyalkylene glycol polymer having n units, wherein n isan integer of 1-50.
 12. The method of claim 1 comprising administeringat least one compound together with one or more pharmaceuticallyacceptable excipients as a pharmaceutical composition.
 13. The method ofclaim 12, which pharmaceutical composition comprises said one or morecompounds in substantially pure form, said substantially pure formconsisting of at least 95% wt. of said one or more compounds and up to5% wt. of free polyalkylene glycol, with the total amount in said formof said one or more compounds and said free polyalkylene glycol being100% wt.
 14. The method of claim 12, which pharmaceutical compositioncomprises said one or more compounds in partially pure form, saidpartially pure form consisting of about 5-60% wt. of the one or morecompounds and about 95-40% wt. of free polyalkylene glycol, the totalamount being 100% wt.
 15. The method of claim 12, wherein saidpharmaceutical composition is formulated as a unit dosage form.
 16. Themethod of claim 12, which the pharmaceutical composition is formulatedfor oral administration.
 17. The method of claim 12, wherein saidpharmaceutical composition is formulated as a unit dosage formcomprising from 0.1 to about 500 mg of the one or more compounds. 18.The method as claimed in claim 1, wherein a daily dose of 1.0 mg to 15 gof said one or more compounds is administered.